Frontline Lurbinectedin Plus Atezolizumab Enhances Survival in ES-SCLC

A clinically meaningful OS benefit was also observed with the addition of lurbinectedin to atezolizumab vs atezolizumab alone, at a median of 13.2 months vs 10.6 months, respectively.

Lurbinectedin (Zepzelca) plus atezolizumab (Tecentriq) as frontline maintenance therapy enhanced progression-free survival (PFS) and overall survival (OS) outcomes vs atezolizumab monotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), according to primary results from the phase 3 IMforte trial (NCT05091567) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

The median PFS with the doublet (n = 242) was 5.4 months (95% CI, 4.2-5.8) by independent review facility (IRF) assessment vs 2.1 months (95% CI, 1.6-2.7) with the monotherapy (n = 241), translating to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.43-0.67; 2-sided P < .0001). The 6-month IRF-PFS rates in the respective arms were 41.2% and 18.7%; at 12 months, these rates were 20.5% and 12.0%.

A clinically meaningful OS benefit was also observed with the addition of lurbinectedin to atezolizumab vs atezolizumab alone, at a median of 13.2 months (95% CI, 11.9-16.4) vs 10.6 months (95% CI, 9.5-12.2), respectively (HR, 0.73; 95% CI, 0.57-0.95; 2-sided P = .0174). The 12-month OS rate with the doublet was 56.3% vs 44.1% with the monotherapy.

“IMforte is the first phase 3 study to show PFS and OS improvement with first-line maintenance treatment for ES-SCLC, highlighting the potential of lurbinectedin plus atezolizumab to become a new standard of care [SOC] for first-line maintenance therapy in patients with this aggressive and difficult-to-treat disease,” Luis Paz-Ares, MD, PhD, of Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, in Madrid, Spain, said in a press briefing ahead of the meeting.

Underscoring the Unmet Need

SCLC represents approximately 15% of all lung cancer cases, and 70% of these cases are extensive-stage disease, according to Paz-Ares. For these patients, SOC treatment is comprised of induction etoposide, platinum, and an immune checkpoint inhibitor (ICI) in the form of atezolizumab or durvalumab (Imfinzi), followed by maintenance treatment with the same ICI. Although patients respond to induction, many will experience early disease progression and poor survival. Earlier phase trials have shown that when lurbinectedin is paired with ICIs, it is active with favorable tolerability.^2-4

Shining a Light on IMforte: Eligibility, Treatment, End Points

The global, open-label, randomized, phase 3 trial enrolled patients with ES-SCLC who had not previously received systemic treatment, who did not have central nervous system metastases, and who have an ECOG performance status of 0 or 1 (n = 660). They received induction treatment with atezolizumab plus carboplatin and etoposide for 4 cycles every 3 weeks.

Patients were screened again and those with an ongoing complete response/partial response or stable disease after induction treatment and an ECOG performance status of 0 or 1 went on to receive maintenance treatment (n = 483). These patients were randomly assigned 1:1 to receive 1200 mg of intravenous atezolizumab every 3 weeks with or without 3.2 mg/m² of lurbinectedin. Treatment continued until disease progression or intolerable toxicity.

Notably, no crossover was allowed. Patients were stratified by performance status (0 vs 1), lactate dehydrogenase (≤ upper limit of normal [ULN] vs > ULN), liver metastases at baseline induction (yes vs no), and receipt of prophylactic cranial irradiation (yes vs no).

The trial’s primary end points were IRF-PFS and OS, and secondary end points comprised investigator-assessed PFS, objective response rate, duration of response, and safety. Efficacy was evaluated from randomization into the maintenance phase of the design. Investigators assessed safety from day 1 of cycle 1 of treatment.

Additional Efficacy Revelations

Investigator-assessed PFS aligned with what was reported with regard to IRF assessment. The median PFS with lurbinectedin plus atezolizumab was 5.4 months vs 2.7 months with atezolizumab monotherapy (stratified HR, 0.55; 95% CI, 0.45-0.68).

Safety Spotlight

All-cause adverse effects (AEs) were reported in 97.1% of those on the combination arm vs 80.8% of those on the monotherapy arm, with 38.0% and 22.1% of these respective effects being grade 3 or 4. Treatment-related grade 3 or 4 AEs were experienced by more patients in the investigative arm vs those in the control arm, at 25.6% vs 5.8%, respectively.

Twelve patients who received the doublet experienced grade 5 AEs vs 6 patients who received the monotherapy; they were treatment related for 2 patients in the investigative arm and 1 patient in the control arm. More serious AEs occurred with the doublet vs the monotherapy (31.0% vs 17.1%).

AEs led to dose interruption or modification of any drug for 38.0% of those in the investigative arm vs 13.8% of those in the control arm; they led to discontinuation of any drug for 6.2% and 3.3% of patients, respectively.

“The safety profile of lurbinectedin plus atezolizumab was manageable, with mostly low-grade AEs and low treatment discontinuation rates,” Paz-Ares said. “No clinically meaningful increase in immune-related AEs was observed [with the addition of lurbinectedin],” he noted.

The most common AEs experienced by at least 10% of those in the lurbinectedin/atezolizumab and atezolizumab-alone arms were nausea (36.4% vs 4.2%), anemia (31.8% vs 6.7%), fatigue (20.2% vs 7.9%), decreased appetite (16.9% vs 6.7%), decreased platelet count (15.3% vs 2.9%), diarrhea (14.0% vs 7.5%), vomiting (13.6% vs 2.5%), asthenia (12.8% vs 6.3%), thrombocytopenia (12.8% vs 1.7%), decreased neutrophil count (12.8% vs 1.3%), constipation (12.0% vs 6.3%), and neutropenia (10.7% vs 1.7%).

“You see a clear increase for those patients treated with lurbinectedin/atezolizumab, particularly AEs related to the lurbinectedin—nausea, vomiting, diarrhea, asthenia, and also some more myelosuppression,” Paz-Ares noted. “Concerning myelosuppression, that was one of the main concerns, we have seen febrile neutropenia only in 1.7% of cases.”

He added that grade 3 or 4 infections and infestations occurred in 6.6% of those who received the doublet vs 5.0% of those who were given the monotherapy.

Topline Takeaway

“I think it’s important to note that at least in the US, lurbinectedin is FDA approved in the second-line setting, and so, with the results of this study, we would anticipate that it would be moved into the first-line maintenance setting—so, moving it into an earlier line before there is progression on the first-line therapy,” Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, commented. “The study is important because both PFS and OS were increased. But I would point out, while this is a next step, PFS is still quite low in both arms, and we need to work on additional ways of advancing this even further. So, it is a small next step; it is extending the time that the tumor doesn’t progress and the amount of time that the patients are living, but we need to do more research in ES-SCLC, as well.”

Disclosures: Paz-Ares listed no disclosures.

References

1. Paz-Ares L, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. Presented at: 2025 ASCO Annual Meeting; May 30-June 3, 2025; Chicago, IL. Abstract 8006.
2. Calles A, Navarro A, Doger de Speville Uribe BG, et al. Lurbinectedin plus pembrolizumab in relapsed SCLC: the phase I/II LUPAR study. J Thorac Oncol. Published online February 10, 2025. doi:10.1016/j.jtho.2025.02.005
3. Aix SP, 2SMALL (NCT04253145) phase I part: lurbinectedine (LUR) in combination with atezolizumab (ATZ) for second line extensive stage small cell lung cancer (ES-SCLC) patients (pts). J Immunother Cancer. 2021;9. doi:10.1136/jitc-2021-SITC2021.464
4. Aix SP, Navarro A, Garcia MEO, et al. Safety and efficacy of lurbinectedin plus atezolizumab as second-line treatment for advanced small-cell lung cancer: results of the 2SMALL phase 1/2 study (NCT04253145). Presented at: 2025 ASCO Annual Meeting; May 30-June 3, 2025; Chicago, IL. Abstract 8013.